ELEMENTS OF NEURAL ADHESION MOLECULES AND A YEAST VACUOLAR PROTEIN SORTING RECEPTOR ARE PRESENT IN A NOVEL MAMMALIAN LOW-DENSITY-LIPOPROTEIN RECEPTOR FAMILY MEMBER

Normal cell development depends to a large part on multifunctional pro teins that have evolved by recombination of proven modular elements. W e now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotei n (LDL) receptor gene family. The extracellular portion of the similar to-250-kDa membrane protein, termed LR11, contains a cluster of 11 LD L receptor ligand binding repeats, a group of 5 LDL receptor ''YWTD'' repeats, a large hexarepeat domain of structural elements found in neu ral cell adhesion molecules, and a domain with similarity to a yeast r eceptor for vacuolar protein sorting, VPS10. The cytoplasmic domain ex hibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abu ndantly in brain, in particular the hippocampus, dentate gyrus, and ce rebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apol ipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The ident ification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunct ional mosaic proteins akin to the ever expanding LDL receptor gene fam ily.